Resurfacing of Sleeve-Like Circumferential Giant Congenital Melanocytic Nevi on the Upper Extremity With Pre-Expanded Pedicled Flap.

As the relative shortage of healthy tissue obviates the option of local soft tissue coverage, reconstruction of circumferential giant congenital melanocytic nevi (GCMN) on the upper extremity remains particularly challenging. Here the authors report a 3-stage procedure involving pre-expanded pedicled flap from the torso for the reconstruction of upper extremity after circumferential GCMN excision in pediatric patients. The giant nevus was completely removed and the size of the excised nevus was 31 × 14.5 cm. The donor site was primarily closed. No major complication was encountered. Reconstruction with expanded pedicled flap achieved satisfactory results, both functionally and cosmetically.

The Efficacy and Safety of Hyaluronic Acid Injection in Tear Trough Deformity: A Systematic Review and Meta-analysis.

BACKGROUND: Hyaluronic acid (HA) injection is an effective method to correct tear trough deformity. Nevertheless, the quantitative data of cosmetic results and complications of HA injection in tear troughs remained unemployed. The purpose of this meta-analysis was to synthesize the current quantitative data on the aesthetic outcomes and adverse effects of tear trough deformity correction with HA injection. METHODS: This meta-analysis consulted PubMed, Embase, Web of Science, Scopus and Cochrane databases based on the search terms published before September 2022. Data extracted was analyzed to evaluate the satisfaction rates and complications of HA injection. Meta-analysis was performed using the random-effect model for overall and subgroup analysis. RESULTS: This meta-analysis comprised 31 reports involving 2556 participants. The pooled overall satisfaction rate was 91.0% (95% CI 84.9-95.7%). The pooled rates of swelling/edema and bruising/ecchymosis were 19.2% (95% CI 10.4-29.9%) and 18.4% (95% CI 10.1-28.4%), respectively. The pooled rates of redness/erythema, contour irregularity/lump and blue discoloration/Tyndall effect were 7.1% (95% CI 1.5-15.6%), 5.3% (95% CI 1.8-10.2%) and 0.9% (95% CI 0.0-2.5%), respectively. CONCLUSIONS: The present meta-analysis manifested a low risk of complication rate and a high satisfaction rate in tear trough rejuvenation with HA injection. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cutaneous Melanoma and 486 Human Blood Metabolites: A Mendelian Randomization Study.

BACKGROUND: Cutaneous melanoma (CM) has long been recognized as a lethal form of cancer. Despite persistent research endeavors, the precise underlying pathological mechanisms remain largely unclear, and the optimal treatment for this patient population remains undetermined. OBJECTIVES: This study aims to examine the causal associations between CM and 486 metabolites. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to ascertain the causal relationship between blood metabolites and CM. The causality analysis involved the inverse variance weighted (IVW) method, followed by the MR-Egger and weighted median (WM) methods. To increase the robustness of our findings, several sensitivity analyses, including the MR-Egger intercept, Cochran's Q test, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were performed. The robustness of our results was further validated in independent outcome samples followed by a meta-analysis. Additionally, a metabolic pathway analysis was carried out. RESULTS: The two-sample MR analysis yielded a total of 27 metabolites as potential causal metabolites. After incorporating the outcomes of the sensitivity analyses, seven causal metabolites remained. Palmitoylcarnitine (OR 0.9903 95% CI 0.9848-0.9958, p = 0.0005) emerged as the sole metabolite with a significant causality after Bonferroni correction. Furthermore, the reverse MR analysis provided no evidence of reverse causality from CM to the identified metabolites. CONCLUSIONS: This study suggested a causal relationship between seven human blood metabolites and the development of CM, thereby offering novel insights into the underlying mechanisms involved. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Six first-line tyrosine kinase inhibitors reveal novel inhibition potential for the EGFR S768I mutation.

Lung cancer, the leading cause of cancer-related mortality, is the most commonly diagnosed cancer. Tyrosine kinase inhibitors (TKIs) are considered a drug-targeted therapy for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, limited data are available involving the activity of EGFR TKIs against rare EGFR mutations. Here, based on an endogenous EGFR-depleted cell Line H3255 by CRISPR, H3255 cells with rare mutant EGFRS768I and compound mutations EGFRS768I+L858R were tested using cell proliferation assay, cytotoxicity, membrane potential, flow cytometry and Western blot analysis. We conducted cytotoxicity screening of EGFR mutations on six front-line TKIs based on first-, second-, and third-generation TKIs (afatinib, dacomitinib, osimertinib, erlotinib, gefitinib, and icotinib). The results showed that the sensitivity of these mutants containing rare variants EGFRS768I to six front-line TKIs was enriched in the irreversible TKI cytotoxicity assays by determining their change in cytotoxicity, apoptosis, cell proliferation and signal pathway factors. Importantly, the variants harboring EGFRL858R (H3255), EGFRS768I (H3255S768I) and EGFRS768I+L858R (H3255S768I+L858R) were sensitive to six TKIs and induced cytotoxicity through different pathways. Moreover, the compound mutations EGFRS768I+L858R showed more TKI resistance than EGFRS768I mutation and EGFRL858R mutation. We present a comprehensive reference for the sensitivity of EGFRS768I variants to six front-line TKIs. For patients with the EGFR S768I mutation and compound mutations EGFRS768I+L858R, six first-line TKIs appear to be reasonable therapeutic options.

"Subzone-Counting" Method in Asian Facial Liposuction: A Retrospective Study.

BACKGROUND: Facial liposuction is a popular and reliable procedure for patients with subcutaneous fat accumulation pursuing the ideal face shape. However, complications like irregularities and asymmetry are still problems for plastic surgeons. To lower the incidence of the above complications, we developed the "subzone-counting" method. In this study, this technique was introduced and evaluated. METHODS: By several lines all parallel to the earlobe-mouth corner line, the liposuction area was subdivided into several subzones. With consistent negative pressure, the paths of the cannula trip in all subzones were also parallel to the earlobe-mouth corner line. An objective index could be obtained by counting the number of aspiration in every subzone. Based on this index, the real-time adjustment was made to achieve smoothness and symmetry. RESULTS: This study identified 32 Chinese patients who accepted this method between January 2019 and January 2021. The follow-up ranged from 6 to 44 months. Twenty-nine and 3 patients were satisfied and somewhat satisfied with the postoperative outcome, respectively. No patient was unsatisfied with the outcome. And no major complication was reported. CONCLUSIONS: The "subzone-counting" method is safe and effective for facial liposuction. The approach helps intraoperative judgment and adjustment. According to the real-time counting results, contour smoothness and bilateral symmetry can be easily achieved and less dependent on the surgeon's experience.

Short Nose Lengthening in Primary and Revision Rhinoplasty in Asians.

BACKGROUND: Surgical techniques and graft materials are important factors for short nose lengthening in both primary and revision rhinoplasty in Asian patients. Other subunit of the nose need to be improved as well to achieve aesthetic perfection. MATERIALS AND METHODS: A cohort of 98 patients who underwent primary and revision rhinoplasty for moderate to severe short nose deformity from January 1, 2019, to December 31, 2020, were enrolled. Nasal elongation was achieved via an open rhinoplasty approach using autologous costal cartilage exclusively for grafting. Aesthetic outcomes were evaluated by anthropometric measurement and satisfaction assessment from patients and physicians. RESULTS: The mean duration of follow-up was 10.6 months. In both primary and revision cases, nasal length relative to preoperative measurements increased significantly, while nasal tip projection did not differ significantly. Columellar-facial angle and nasofrontal angle decreased significantly in both groups. Both physicians and patients reported improvement in aesthetic outcomes. CONCLUSIONS: Aesthetic satisfaction was reported from both patients and physicians. Autologous costal cartilage is an ideal graft material that offers strong structural support. Caudal septal extension graft using autologous costal cartilage sandwiched by extended spreader grafts achieve satisfactory lengthening of the central compartment and also increase nasal tip projection and rotation.

A Combination Method of Costal Cartilage Injection Techniques for Augmentation Rhinoplasty.

BACKGROUND: The multiple toothpick-shaped costal cartilage (MTCC) injection technique was introduced as an improvement based on the free diced costal cartilage (FDCC) injection technique for augmentation rhinoplasty. However, radix irregularities may occur when using the MTCC technique. Considering that the FDCC grafts are easier to shape at the nasal radix, we adopted a combination method of the 2 techniques to achieve natural and smooth contour. METHODS: Four patients accepted this method for augmentation rhinoplasty. Through a unilateral marginal incision, the costal cartilage grafts were injected for nasal augmentation at the subperiosteal plane. The FDCC grafts and the MTCC grafts were used for nasal radix and dorsum augmentation, respectively. Nasal contour was adjusted by external shaping. The follow-up ranged from 24 to 43 months. RESULTS: All patients were satisfied with the surgical outcome. There were no major complications occurred during the follow-up. One patient underwent rasping revision due to her own beauty-appreciation changes. CONCLUSIONS: The combination method can take advantages of the FDCC and MTCC injection techniques. It can effectively lower the incidence of contour irregularities and graft displacement. Meanwhile, it is easy to perform without special procedure, and is time-saving and cartilage-saving.

The Ideal Nasal Tip Projection and Rotation Angles in Chinese: A Preference Analysis of the General Population.

ABSTRACT: Rhinoplasty to reshape the nasal tip is increasingly popular among Chinese women. Aesthetic standards vary across different ethnic groups and it is key to identify preferences for the ideal nasal tip in China to set surgical goals. Therefore, we administered an online survey to plastic surgeons and the public through social media to rank nasal tip images by aesthetic preference. Images were created from a single photograph to show various dimensions of nasal tip projection to nasal dorsum length ratio (NTP/NDL) and nasal labial angle (NLA). Preferences were compared by age, sex, living area, ethnic background, occupation, and history of plastic procedures on respondents' preferences. Overall, there were 703 respondents, including 441 (63%) women and 50 plastic surgeons. Nasal tip projection to nasal dorsum length ratio of 0.63 was ranked highest by all demographic groups, including women (47%), men (50%), and plastic surgeons (66%). Nasal labial angle of 106° was first choice overall and preferred by 34%, 34%, and 52%, respectively. Preferences followed a bell curve for NTP/NDL and NLA, with lower rates of preference as parameters diverged further from the first choice. The preference for NTP/NDL of 0.63 and NLA of 106° was conserved across surgeons, lay people, and all demographic groups. The authors suggest that these proportions could be used as reference for preoperative design in rhinoplasty.

A Survey of Factors Influencing Specialization in Plastic Surgery Among Chinese Surgeons.

ABSTRACT: In recent years, more Chinese surgeons have left other fields to enter plastic surgery. The factors influencing this respe-cialization have not been elicited. The authors aim to elucidate Chinese surgeons' experience and career satisfaction in this specialty change. Between July and September 2020, the authors conducted an online survey of nonplastic surgeons who received plastic surgery training at an academic center. The survey evaluated their motivation for pursuing their field, practice patterns, and career satisfaction. Responses were compared those who respecialized in plastic surgery with those who did not. A total of 251 nonplastic surgeons completed the survey. The most frequent reasons for pursuing plastic surgery were lifestyle (61.1%), desire to help others (44.4%), and higher compensation (37.3%). Among those who changed fields, employment in academic centers declined from 85% to 51.7%, 70% devoted at least half of their practice to aesthetic surgery, and the median nights on call decreased from 1.54 to 0.38 per week after specializing in plastic surgery. Overall career satisfaction in plastic surgery was significantly higher compared with their former specialties (78.3% versus 28.3%, P 0.05). The authors' study showed that outflow of surgeons from other specialties to plastic surgery is mainly due to burnout, which erodes physicians' satisfaction level and the quality of care they are able to provide. The authors highlight the need for reducing burnout in other surgical fields as well as rigorous plastic and aesthetic surgery training for those changing fields to ensure high-quality patient care.

Comparison of Free Diced and Multiple Toothpick-Shaped Costal Cartilage Injection Techniques for Augmentation Rhinoplasty.

BACKGROUND: The free diced costal cartilage (FDCC) injection technique has been used in the augmentation rhinoplasty for a long time. In order to lower the incidence of nasal contour irregularities and graft displacement, we developed the multiple toothpick-shaped costal cartilage (MTCC) injection technique. This comparative study was conducted to introduce and assess this new technique. METHODS: This retrospective analysis included 51 patients who underwent augmentation rhinoplasty with either the FDCC or MTCC injection technique at the 17th Department of Plastic Surgery in the Plastic Surgery Hospital between July 2014 and May 2020. The patients were divided into the FDCC (n = 30, 58.82%) and MTCC (n = 21, 41.18%) groups. General data, postoperative patient satisfaction, complications and revision rate were compared between the groups. RESULTS: Except for the follow-up period, there were no significant differences in general data (age, sex, preoperative dorsum deformity, preoperative rhinoplasty history) between the groups. Postoperative patient satisfaction, complications and revision rate were similar between the two groups. CONCLUSIONS: The MTCC injection is a safe and effective technique for augmentation rhinoplasty. Like the FDCC injection technique, the new technique is relatively easy to perform and time-saving with concealed scarring and minimal postoperative edema. Most of its revision surgeries are also easy to perform by simple rasping and reinjection. According to our experience, the new technique may have wider indication as well as lower incidence of nasal contour irregularities and graft displacement. Therefore, we suggest that the MTCC injection technique is reliable and worthy of recommendation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Analysis of genome-wide DNA methylation patterns in obesity.

Obesity is a chronic and complex psychosomatic disease that is becoming increasingly prevalent worldwide. This study aimed to analyze whole methylation profiles to uncover the epigenetic mechanisms associated with obesity. DNA methylation profiles in blood samples from patients with obesity and normal controls were studied using the Illumina 850 K methylation microarray. The diagnostic value of the differentially methylated genes was determined using receiver operating characteristic (ROC) analysis. The expression of selected candidate genes was verified using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and pyrosequencing. A total of 9,371 significantly differentially methylated sites (7,974 hypermethylated sites and 1,397 hypomethylated sites) were identified in 4,571 genes. A difference in the distribution of differentially methylated sites (hypermethylated and hypomethylated) in both gene structures and CpG islands was observed. A total of 114 key differentially methylated sites were identified in the CpG islands. ROC results indicated that Inhibin Subunit Beta B (INHBB), Homeobox A9 (HOXA9), Troponin T3 (TNNT3), Cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) and Zinc finger and BTB domain-containing 7 B (ZBTB7B) could discriminate patients with obesity from normal controls. RT-qPCR results of CRTC1 and ZBTB7B were consistent with our methylation profile results. The pyrosequencing results showed that the methylation levels of CRTC1 CpG sites (CpG1 and CpG2-cg11660071) and INHBB CpG sites (CpG2) were significantly changed in patients with obesity compared with normal controls, which was consistent with our DNA methylation profile results. Our study provides new insights into the pathological mechanism of obesity.

Reconstruction of Circumferential Upper Extremity Defect Using a Bipedicle Expanded Flank Flap.

BACKGROUND: Resurfacing of extensive upper extremity lesions remains a challenge for plastic surgeons because of optimal functional and aesthetic outcomes and limitations of flap size. We introduced a pre-expanded flank flap to reconstruct the circumferential upper extremity defect in one sequence of tissue expansion. METHOD: Between March 2015 and June 2019, 14 consecutive patients underwent reconstructive treatment for circumferential soft tissue lesions in the upper extremity using a bipedicle expanded flank flap. Surgical treatment was divided into 3 stages consisting of expander implantation in the flank area, bipedicle flap transfer to resurface the skin lesion on upper extremity, and flap pedicle transection. Flap survival, complications, and functional and aesthetic outcomes were evaluated. RESULT: Fourteen patients with circumferential upper extremity lesions were enrolled in this study, 2 of them were diagnosed as extensive scar and 12 of them as giant congenital melanocytic nevi. Twelve patients completed more than 6-month follow-up. One or 2 tissue expanders were implanted in flank, lateral thorax, or abdomen area. The average time of tissue expansion was 25.9 weeks. The pedicled thoracoabdominal flaps were used to resurface a mean skin defect area of 406.6 cm2 ranging from 252 to 660 cm2. In all cases, primary donor site closure was achieved. Seroma developed in 1 case after flap transferred. With aspiration, the flap survived completely. No marginal necrosis was seen. The reconstructed limbs showed satisfactory outcome in both aesthetic and functional aspects. CONCLUSIONS: The bipedicle expanded flank flap enables reconstruction of circumferential upper limb skin lesions in 1 sequence of tissue expansion with low complication rate and high patient satisfaction.

Artificial Intelligence in Plastic Surgery: Applications and Challenges.

New developments in artificial intelligence (AI) offer opportunities to enhance plastic surgery practice, research, and education. In this article, we review relevant AI tools and applications, including machine learning, reinforcement learning, and natural language processing. Our own Markov decision process for keloid treatment illustrates how these models are developed and can be used to enhance decision-making in clinical practice. Finally, we discuss challenges of implementing AI and knowledge gaps that must be addressed to successfully apply AI in plastic surgery. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Effect of cumulative fluid balance on acute kidney injury and patient outcomes after orthotopic liver transplantation: A retrospective cohort study.

AIM: Acute kidney injury (AKI) is a serious complication following orthotopic liver transplantation (OLT) and it affects long-term patient survival. The aims of this study were to identify the effects of cumulative fluid balance (FB) on early post-OLT AKI and adverse outcomes and to construct a model to predict AKI. METHODS: We retrospectively analysed 146 adult patients who underwent OLT. AKI severity was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Univariate and multivariate logistic regression analyses were used to evaluate the association between cumulative FB and post-OLT AKI. The Kaplan-Meier method was used to estimate the survival rate. RESULTS: Within the perioperative period of 72 hours, 50% (66/132) of patients developed AKI, with 36 (54%), 16 (24%) and 14 (21%) patients having AKI stages 1, 2 and 3, respectively. The cumulative FB was the risk factors for post-OLT AKI (odds ratio [OR], 1.011; 95% confidence interval [CI], 1.156~6.001; P = .021). Preoperative albumin was a protective factor for post-OLT AKI (OR, 0.309; 95% CI, 0.140~0.731; P = .007). The AKI group requires renal replacement therapy (RRT) more (15.2% vs 0%, P = .001) and associated with postoperative complications (56% vs 28.8%, P = .003). The complication-free survival was lower in the AKI group ([11.90 vs 18.74] months, χ2 = 9.60, P = .002). CONCLUSION: Cumulative FB within 72 hours is associated with post-OLT AKI and requires RRT. Cumulative FB impacts the long-term complication-free survival of the recipients.

Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/ß-catenin pathway in pancreatic cancer cells.

The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/ß-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling.

BACKGROUND/AIMS: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. METHODS: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. RESULTS: SFN can inhibit pancreatic cancer cell growth， promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. CONCLUSION: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.

Potential Safety Loophole of Fat Grafting in Breast Cancer Patients.

UNLABELLED: Autologous fat grafting (AFG) accounts for 9.1 % of all cosmetic surgical procedures in the world. Its use has been increasing tremendously in breast reconstruction and produces satisfying outcomes. However, the lack of standard guidelines for routine screening protocols in breast cancer patients before and after AFG warrants consideration of the safety of AFG use in post-mastectomy and post-lumpectomy reconstruction. This manuscript examines AFG in breast reconstruction publications and details the complications, the mechanism of AFG, as well as the relationship between adipose stem cells (ASCs) and cancer recurrence. The ASCs transferred in AFG act as multiple potent stem cells, which can impact cancer recurrence in various ways. Both in vitro and in vivo studies show that ASCs can stimulate the recurrence of breast cancer. Based on a review of existing evidence, we provide recommendations and guidelines for AFG use in breast reconstruction to aid in clinical decision-making. Further investigations are needed to evaluate the long-term clinical safety of AFG as well as the proposed guidelines. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects. METHODS: In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo. RESULTS: Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model. CONCLUSIONS: Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.

Beverage consumption and facial skin aging: Evidence from Mendelian randomization analysis.

BACKGROUND: Observational studies have linked coffee, alcohol, tea, and sugar-sweetened beverage (SSB) consumption to facial skin aging. However, confounding factors may influence these studies. The present two-sample Mendelian randomization (MR) investigated the potential causal association between beverage consumption and facial skin aging. METHODS: The single-nucleotide polymorphisms (SNPs) associated with coffee, alcohol, and tea intake were derived from the IEU project. The SSB-associated SNPs were selected from a genome-wide association study (GWAS). Data on facial skin aging were derived from the largest GWAS involving 16 677 European individuals. The inverse variance-weighted (IVW) was the main MR analysis method, supplemented by other methods (MR-Egger, weighted median, simple mode, and weighted mode). The MR-Egger intercept analysis was used for sensitivity analysis. Moreover, we conducted a replication analysis using data from another GWAS dataset on coffee consumption to validate our findings. RESULTS: Four instrumental variables (IVs) sets were used to examine the causal association between beverage consumption (coffee, alcohol, tea, SSB) and facial skin aging. Our results revealed that genetically predicted higher coffee consumption reduced the risk of facial skin aging (OR: 0.852; 95% CI: 0.753-0.964; p = 0.011, IVW method). The sensitivity analysis confirmed the robustness of the findings, with no evidence of pleiotropy or heterogeneity. The results of replicated MR analysis on coffee consumption were consistent with the initial analysis (OR = 0.997; 95% CI = 0.996-0.999; p = 0.003, IVW method). CONCLUSIONS: This study manifests that higher coffee consumption is significantly associated with a reduced risk of facial skin aging. These findings can offer novel strategies for identifying the underlying etiology of facial skin aging.

Electroacupuncture pretreatment preserves telomerase reverse transcriptase function and alleviates postoperative cognitive dysfunction by suppressing oxidative stress and neuroinflammation in aged mice.

BACKGROUND: Elderly patients often exhibit postoperative cognitive dysfunction (POCD), a postsurgical decline in memory and executive function. Oxidative stress and neuroinflammation, both pathological characteristics of the aged brain, contribute to this decline. This study posits that electroacupuncture (EA) stimulation, an effective antioxidant and anti-inflammatory modality, may enhance telomerase reverse transcriptase (TERT) function, the catalytic subunit of telomerase known for its protective properties against cellular senescence and oxidative damage, to alleviate POCD in aged mice. METHODS: The animal POCD model was created by subjecting aged mice to abdominal surgery, followed by EA pretreatment at the Baihui acupoint (GV20). Postoperative cognitive function was gauged using the Morris water maze (MWM) test. Hippocampal TERT mRNA levels and telomerase activity were determined through qPCR and a Telomerase PCR ELISA kit, respectively. Oxidative stress was assessed through superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA) levels. Iba-1 immunostaining determined the quantity of hippocampal microglia. Additionally, western blotting assessed TERT, autophagy markers, and proinflammatory cytokines at the protein level. RESULTS: Abdominal surgery in aged mice significantly decreased telomerase activity and TERT mRNA and protein levels, but increased oxidative stress and neuroinflammation and decreased autophagy in the hippocampus. EA-pretreated mice demonstrated improved postoperative cognitive performance, enhanced telomerase activity, increased TERT protein expression, improved TERT mitochondrial localization, and reduced oxidative damage, autophagy dysfunction, and neuroinflammation. The neuroprotective benefits of EA pretreatment were diminished following TERT knockdown. CONCLUSIONS: Our findings underscore the significance of TERT function preservation in alleviating surgery-induced oxidative stress and neuroinflammation in aged mice. A novel neuroprotective mechanism of EA stimulation is highlighted, whereby modulation of TERT and telomerase activity reduces oxidative damage and neuroinflammation. Consequently, maintaining TERT function via EA treatment could serve as an effective strategy for managing POCD in elderly patients.